Comparison of 68Ga-FAPI and 18F-FDG PET/CT for the diagnosis of primary and metastatic lesions in abdominal and pelvic malignancies: A systematic review and meta-analysis

Purpose The purpose of this study is to compare the application value of 68Ga-FAPI and 18F-FDG PET/CT in primary and metastatic lesions of abdominal and pelvic malignancies (APMs). Materials The search, limited to the earliest available date of indexing through 31 July 2022, was performed on PubMed, Embase, and Cochrane Library databases using a data-specific Boolean logic search strategy. We calculated the detection rate (DR) of 68Ga-FAPI and 18F-FDG PET/CT in the primary staging and recurrence of APMs, and pooled sensitivities/specificities based on lymph nodes or distant metastases. Results We analyzed 473 patients and 2775 lesions in the 13 studies. The DRs of 68Ga-FAPI and 18F-FDG PET/CT in evaluating the primary staging and recurrence of APMs were 0.98 (95% CI: 0.95-1.00), 0.76 (95% CI: 0.63-0.87), and 0.91(95% CI: 0.61-1.00), 0.56 (95% CI: 0.44-0.68), respectively. The DRs of 68Ga-FAPI and 18F-FDG PET/CT in primary gastric cancer and liver cancer were 0.99 (95% CI: 0.96-1.00), 0.97 (95% CI: 0.89-1.00) and 0.82 (95% CI: 0.59-0.97), 0.80 (95% CI: 0.52-0.98), respectively. The pooled sensitivities of 68Ga-FAPI and 18F-FDG PET/CT in lymph nodes or distant metastases were 0.717(95% CI: 0.698-0.735) and 0.525(95% CI: 0.505-0.546), and the pooled specificities were 0.891 (95% CI: 0.858-0.918) and 0.821(95% CI: 0.786-0.853), respectively. Conclusions This meta-analysis concluded that 68Ga-FAPI and 18F-FDG PET/CT had a high overall diagnostic performance in detecting the primary staging and lymph nodes or distant metastases of APMs, but the detection ability of 68Ga-FAPI was significantly higher than that of 18F-FDG. However, the ability of 68Ga-FAPI to diagnose lymph node metastasis is not very satisfactory, and is significantly lower than that of distant metastasis. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42022332700.


Introduction
In recent years, the incidence and mortality of cancer have increased. An estimated 1,918,030 new cancer cases and 609,360 cancer deaths are expected in the United States, as published on January 12, 2022 (1). In the abdominal and pelvic malignancies (APMs), the proportions of liver cancer (LC), gastric cancer (GC), pancreatic cancer, colorectal cancer, and female reproductive system tumors are relatively high (1). Therefore, extensive clinical and basic research to strengthen the mission of health, extend life expectancy, and reduce the burden of disease and disability is crucial. Early diagnosis and accurate evaluation of treatment decisions and prognoses are of great significance (2). Given this fact, researchers have been stepping up their efforts to address these clinical issues (3).
The tumor microenvironment (TME) is a complex and dynamic framework that plays a key role in the survival, proliferation, spread and drug resistance of malignant cells through tumorigenic signaling pathways (4)(5)(6). Recently, the cancer-promoting role of the TME has become an the issues of interest to scientists (3). The tumor stroma is the main component of tumor lesions and has common components among various types of cancer (3). In addition to affecting tumor cells, the TME also affects a variety of nonmalignant cells (including immune cells, endothelial cells, epithelial cells, fibroblasts, and adipocytes), which are coordinated through complex, dynamic networks of different cytokines and chemokines (5,7). A series of previous studies have led to a shift in the current research focus and direction of drug development from "tumor" to TME elements, which has aroused researchers' interest in potential molecular imaging applications and therapies (8). Cancer-associated fibroblasts (CAFs) are an extremely heterogeneous and plastic cell population with different sources, functions and surface markers, which exist in various types of malignant solid tumors and are highly expressed, closely related to tumor progression, invasion and metastasis, and have become an attractive target for the TME (6,9). However, when it is not expressed or is underexpressed in the stroma of normal tissues and benign tumors (10), it can usually be identified by fibroblast activating protein (FAP) as a marker (11). FAP, a type II membrane-bound glycoprotein with dipeptidyl peptidase and endopeptidase activities, is highly expressed in the membranes and stroma of CAFs, especially in approximately 90% of epithelial tumors (10), such as liver, colorectal, ovarian, and pancreatic cancers (2,12,13). In this case, using FAP as a CAF identifier and designing FAP-specific PET radiotracers and therapeutic radioligands are some of the results of efforts over the years (3). Therefore, FAP is an important and promising target for cancer therapy (14). In recent years, FAP inhibitors (FAPIs) have become a new targeted molecular probe in nuclear medicine and have attracted much attention in cancer diagnosis and treatment. Currently, dozens of radiopharmaceuticals targeting FAP have been developed, such as FAPI-01, FAPI-2, FAPI-04, FAPI-42, FAPI-46, and FAPI-74 (15)(16)(17)(18). In a recent study, high-quality images were obtained using gallium-68-FAPI-04 positron emission tomography/computed tomography ( 68 Ga-FAPI-04 PET/CT) showing good biodistribution properties and a high tumor background ratio in 28 tumors, including abdominal and pelvic tumors (19).
Recent years have seen an explosion in publications on 68 Ga-FAPI, and FAPI imaging has opened a new chapter in molecular imaging for tumors and nontumor (6). Several studies have demonstrated 68 Ga-DOTA-FAPI to be useful for diagnosing and differentiating primary tumors, detecting metastases, and performing image-guided intervention (20-24). However, its clinical effects and indications are not fully established (6). Fluorine-18-fluorodeoxyglucose ( 18 F-FDG) PET/CT is an important imaging tool for preoperative systematic evaluation, tumor staging, and analysis of the efficacy of tumor treatment (25). However, 18 F-FDG PET/CT imaging has certain limitations for some tumors, such as gastric mucinous adenocarcinoma, well-differentiated hepatocellular carcinoma, and renal cell carcinoma (25). Recently, 68 Ga-FAPI and 18 F-FDG imaging in various tumors has been studied to confirm the advantages and disadvantages of the two methods. FAPI is considered a promising molecular imaging agent because both of these studies confirm that 68 Ga-FAPI can assess the primary tumor stage and detect lymph nodes in addition to distant metastases better than 18 F-FDG (24,(26)(27)(28)(29)(30). Due to different sample sizes, uneven quality, and geographical influences, these results exhibit a high heterogeneity. The authors of a meta-analysis published in 2021 concluded that 68 Ga-FAPI PET imaging was good at diagnosing primary and distant metastases in tumors and non-tumors (3). However, the study included only a few articles and did not include many valuable new papers published after March 2021. The results should also be interpreted cautiously because they are based on a heterogeneous set of studies.
Therefore, to further evaluate which of 68 Ga-FAPI and 18 F-FDG PET/CT were better in tumors, the aim of our study was to compare the application of 68 Ga-FAPI and 18 F-FDG PET/CT in primary and metastatic lesions of APMs.

Materials and methods
This meta-analysis was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. This project was registered in the PROSPERO database (registration number: CRD42022332700).

Data sources and search strategy
We performed electronic literature searches of the PubMed, Embase, and Cochrane Library databases for English-language articles from the earliest available date of indexing through July 31, 2022. The search was performed using a data-specific Boolean logic search strategy using the following keywords: FAP, FAPI, fibroblasts, cancer-associated fibroblasts, CAF, PET, PET/CT, PET-CT, FDG, fluorodeoxyglucose, and positron emission tomography. To obtain more comprehensive search information, we also manually searched the reference lists of identified publications. The search process was performed independently by the two reviewers (XL and HTL).

Inclusion and exclusion criteria
Published articles that met the following conditions were included in the analysis.
(1) 68 Ga-FAPI and 18 F-FDG PET/CT were evaluated simultaneously as diagnostic methods for APMs (primary tumor, lymph node involvement, and distant metastasis). Abdominal and pelvic lesions refer to tumors of the liver, pancreas, gallbladder, spleen, gastrointestinal tract, urinary system, female reproductive system and adrenal glands.
(2) The lesions were confirmed by histopathology or combined clinical/imaging follow-up.
(3) Sufficient data were provided to calculate the number of positive cases with respect to the primary APM tumor, or true-positive, false-positive, false-negative, and true-negative of non-primary tumors (lymph nodes or distant metastases).
The exclusion criteria were as follows: (1) overlapping papers; (2) review articles, animal experiments, editorials or letters, comments, and conference proceedings; (3) a lack of access to the full text; and (4) a sample size of fewer than 10 patients or lesions.

Quality assessment
Two reviewers (XL and HTL) independently evaluated each eligible article's methodological quality. Any disagreements were resolved through consultation or intervention by the third reviewer. The evaluation is based on the modified Quality Assessment of Diagnostic Accuracy Studies version 2 (QUADAS-2), as recommended by the Cochrane Collaboration (31). Each item was evaluated as "high", "low", or "unclear".

Data extraction
Data extraction was carried out for the remaining articles that met the criteria. For each study, we extracted the following data: first author name, year of publication, country, study design (prospective, retrospective), type of APM, diagnostic criteria, imaging purpose, image interpretation, age, sex, sample size, PET/CT scan range, type of imaging agent, injection activity, interval between the FAPI and FDG scans, maximum standardized uptake value (SUVmax) and tumor-to-background ratio (TBR) of the primary lesion, type of image analysis (qualitative, quantitative or semiquantitative), adverse events of imaging agents.
We recorded or calculated the specificity (SEN), sensitivity (SPE), and accuracy per patient and per lesion. When literature evaluation included multiple malignancies such as those of the neck, chest and abdomen, we only extracted data from abdominal tumors. If the abdominal tumor had fewer than 10 patients or lesions, the article was abandoned. When both primary and non-primary tumors (metastases) were evaluated, these data were collected for subgroup analysis. The authors were not contacted to retrieve unpublished data. Data were cross-checked and any discrepancies were discussed to reach a consensus (XL, HTL and CLG).

Statistical analysis
This study collected data for each eligible study. Descriptive statistics and frequency tables were used to summarize the data.
The analysis was performed with subgroups of primary and nonprimary tumors, and diagnostic pooled assessments of 68 Ga-FAPI and 18 F-FDG PET/CT were performed in the subgroups. On a patientlevel basis, we evaluated the value of 68 Ga-FAPI and 18 F-FDG PET/ CT in primary tumors, including primary staging and recurrence. Non-primary tumors, including lymph node, peritoneum, liver, bone and other metastases, were evaluated at the lesion-based level. The primary objective of this study was to evaluate the application value of 68 Ga-FAPI and 18 F-FDG PET/CT in the primary staging and recurrence of APMs using the detection rate (DR). In addition, we separately evaluated the detection value of 68 Ga-FAPI and 18 F-FDG PET/CT in the primary staging of GC and LC. DR was defined as the ratio between the number of patients or lesions with at least one suspected lesion detected by the imaging facility and the total number of abdomen-pelvic malignancy patients who underwent the scan. The secondary objective of this study was to evaluate the SEN, SPE, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of 68 Ga-FAPI and 18 F-FDG PET/CT in metastatic lesions of APMs. A bivariate normal random-effects model for measures was used to analyze and pool the summary points for sensitivity and specificity and their 95% confidence intervals (CIs). The hierarchical summary receiver-operating characteristic (SROC) model was used performed to draw SROC curves and calculate the area under the curve (AUC). I 2 and Cochran's Q homogeneity tests were used to evaluate the consistency of the data (the higher the inconsistency, the greater the uncertainty of the meta-analysis results). According to Higgins JPT et al. (32) in 2003, heterogeneity was divided into low, medium and high levels, expressed with I 2 as 25%, 50% and 75%, respectively. Multiple factors may lead to heterogeneity bias, and no single value is recommended for further analysis. We defined low/medium heterogeneity as acceptable (i.e., I2<50%). In the case of significant heterogeneity between studies, subgroup analysis or meta-regression was performed to analyze the data to determine the source of heterogeneity. As described by Deeks and colleagues (33), we examined the possibility of publication bias by using an effective sample size funnel plot and a regression test of asymmetry. Tests for significance were two-tailed, with a statistically significant P value threshold of 0.05. All statistical analyses were carried out using Stata version 16

Literature search and study selection
A total of 452 articles were retrieved from the PubMed/ MEDLINE, Embase and Cochrane Library databases. Two hundred and twenty-three duplicate articles were excluded. Titles and abstracts were screened according to the established inclusion and exclusion criteria, 208 articles were deleted, leaving 15 papers, and a full-text search was conducted. Full-text reading was conducted, and 13 articles were finally eligible for meta-analysis. The detailed process of literature screening is shown in Figure 1.
PET/CT was used as the imaging mode in all included studies. Seven studies (2,12,17,26,27,29,34) reported the PET/CT scanning scope, mostly from the head to the mid-upper thighs. The 68 Ga-FAPI and 18 F-FDG imaging scans were performed within a week of each other. 68  All studies compared the SUVmax or TBR values of 68 Ga-FAPI and 18 F-FDG PET/CT in primary tumors, we found that FAPI-SUVmax was higher than FDG-SUVmax in most of them, and only the Komek et al. (26) study had a lower FAPI-SUVmax than FDG-SUVmax (mean: 11.54 vs. 18.93). All participants tolerated the 68 Ga-FAPI PET/CT scan. No 68 Ga-FAPI-related pharmacological effects or physiological responses occurred (12,17,28,35). Furthermore, the authors of all the articles declared no conflicts of interest. The main characteristics of the 13 studies included in the meta-analysis are shown in Tables 1, 2.

Risk of bias and applicability
The risk of bias and applicability concerns for the included studies were assessed using QUADAS-2 ( Figure 2). None of the studies were of low quality, and the overall quality of the studies was satisfactory.   Figure 3A). The difference between the two groups was statistically significant (P =0.00).
The DRs of 68   respectively ( Figures 3C, D). Due to the limited sample size, we did not assess the DR of 68 Ga-FAPI and 18 F-FDG PET/CT in recurrence of GC and LC.

Based on non-primary tumor performance analysis
The pooled SENs of 68

Publication bias
Egger's regression intercepts for DR pooling of 68 Ga-FAPI and 18 F-FDG PET/CT in primary tumor performance analysis were 0.317 (95% CI: -0.57 to 0.86, p=0.664) and 1.14 (95% CI: -3.68 to 1.47, p=0.358), respectively, indicating that publication bias was absent. Moreover, the funnel plots for both modalities were symmetric ( Figures 5A, B). Analysis of non-primary tumors by 68 Ga-FAPI and 18 F-FDG PET/CT according to the linear regression detection method suggested regression coefficients of 3.52 (p=0.77) and 0.69 (p=0.92), respectively, indicating that there was no publication bias in the included studies (Figures 5C, D).

Discussions
This is the first study to conduct a head-to-head comparison of 68 Ga-FAPI with 18 F-FDG PET/CT in APM using a meta-analysis. Based on our results, 68 Ga-FAPl performed better than 18 F-FDG in APM primary staging, with DRs of 98% and 70%, respectively. There was no interstudy heterogeneity, indicating that our results were stable and reliable. A previous meta-analysis included the assessment of various cancers, including glioblastoma, head and neck tumors, and nasopharyngeal carcinoma, and the researches believed that the sensitivity of 68 Ga-FAPI in identifying primary tumors was 100% (95%CI: 98%-100%) (6). In addition, when they analyzed abdominal tumors as a subgroup, the sensitivity 68 Ga-FAPI was 100% for primary tumors and 87% for non-primary tumors, indicating the high diagnostic efficacy of this molecule.
In addition, this meta-analysis also evaluated the application value of 68 Ga-FAPI and 18 F-FDG in disease recurrence in APM, and the combined DR was 91% and 56%, respectively. In a retrospective study, the authors analyzed 16 patients with recurrent gastrointestinal tumors (28). They found that the positive rates of 68 Ga-FAPI-04, 18 F-FDG PET/CT and conventional evaluation were 100%, 57.1%, and 33.3%, respectively. Siripongsatian et al. (13) reported that the uptake-positive rates in locally recurring and residual tumor lesions were 46.7% (7/15) on 18 F-FDG PET/CT and 100% (15/15) on 68 Ga-FAPI PET/CT. Compared with the 18 F-FDGbased TNM staging system, the 68 Ga-FAPI-based TNM staging system was upgraded in 6 patients (6/23, 26.1%), resulting in management changes in 2 patients (2/23, 8.7%) (12). Their results also indicated that 68 Ga-FAPI PET/CT was superior to 18 F-FDG in detecting primary and metastatic lesions. Researchers in Thailand (13) and China (28) showed that 68 Ga-FAPI PET/CT was more sensitive than 18 F-FDG in the identification of liver and gastrointestinal primary tumors (100% vs. 52% and 100% vs. 53%). It seems that all published studies thus far support the evidence that 68 Ga-FAPI PET/CT has a higher detection value than 18 F-FDG for primary tumors, and our meta-analysis results indicate the same. This finding is mainly attributed to the excellent biodistribution characteristics of FAPIs, which can provide a better TBR and yield detailed anatomical maps (34). In addition to the higher tracer uptake of 68 Ga-FAPI, the superior performance of 68 Ga-FAPI PET/CT includes its enhanced ability to detect small metastases (diameter<1.0 cm). Tumor lesions >1-2 mm require the formation of a supportive stroma, and since the stroma volume may be larger than the tumor volume, stromal targeted PET imaging may be more sensitive than glycolytic targeted PET imaging in detecting small lesions (2).
All studies compared SUVmax or TBR values in the primary tumor. We found that the vast majority of 68 Ga-FAPI values were higher than those of 18 F-FDG, and only the Komek et al. (26) study had a lower FAPI-SUVmax than FDG-SUVmax (mean: 11.54 vs. 18.93) but failed to demonstrate a significant difference in terms of TBR. The possible reason is that the researchers evaluated patients with colorectal cancer, and hemorrhoid lesions reaching the anal canal showed a higher 18 F-FDG than 6 8 Ga-FAPI uptake. He morrhoids may show increased radioactivity concentration on 18 F-FDG PET/CT but their SUVmax is lower on 68 Ga-FAPI PET/CT than on 18 F-FDG PET/CT (26). The cause of abnormal FAPI concentrations in hemorrhoids may be associated with mild fibrous tissue hyperplasia due to inflammation of various veins and the anal canal (36). Whether the high sensitivity and specificity of FAPI for tumor stroma confer any clinical value beyond a numerical advantage in the TBR is still unknown (26).
Our results showed that the DRs of the imaging agent 68 Ga-FAPI in GC and LC were 99% and 97%, respectively, which were higher than those of the imaging agent 18 F-FDG (82% and 80%). In Israel's (35) small cohort study, 68 Ga-FAPI was superior to 18 F-FDG in detecting primary GC, with a DR of 100%, while that of 18 F-FDG was only 50%. This shows that the high DR of 68 Ga-FAPI is mainly due to the degree GC of differentiation and the known limitations of 18 F-FDG in examining several GC subtypes, such as mucinous adenocarcinoma, noninterstitial diffuse carcinoma, and signed-ring cell carcinoma, raising the possibility that 68 Ga-FAPI can be used as a radiotracer of choice in the evaluation of GC. In addition, the physiological uptake of 18 F-FDG by the gastric wall also further limits the application of 18  Studies have reported a low FDG uptake in signet-ring cell carcinoma and mucinous carcinoma than in conventional adenocarcinoma, which may be due to the low expression of glucose transporter 1 (37)(38)(39).
Similarly, 68 Ga-FAPI PET/CT is superior to 18   higher uptake of FAPI by primary tumors and the lower hepatic background activity of FAPI compared with 18 F-FDG. For hepatocellular carcinoma (HCC) with low expression of glucose transporter-1 and high expression of glucose-6-phosphatase, 40% of such HCC lesions appeared nonavid on FDG PET images (40). The tumor-to-nontumour liver uptake ratio of the well-differentiated HCC was approximately 1.1, indicating that 18 F-FDG PET imaging is difficult to distinguish between the uptake of well-differentiated HCC lesions and healthy liver tissues (41). In addition, investigators observed that 68 Ga-FAPI-04 uptake was higher in most primary intrahepatic cholangiocarcinoma lesions than in HCC lesions (2). This finding may be attributed to the fact that intrahepatic cholangiocarcinoma is a particular type of fibroproliferative tumor and because the number of CAFs tends to significantly exceed that of actual cholangiocarcinoma cells (42). The severity of the corresponding pathological grade of the primary tumor was positively correlated with the 68 Ga-FAPI-04 uptake activity of the lesion (2). Therefore, 68 Ga-FAPI can be useful in assessing the extent of disease and differentiating benign from malignant lesions, especially when assessment is difficult with 18 F-FDG or conventional imaging. In view of the above discussion and analysis, 68 Ga-FAPI seems to be a promising imaging model that may replace 18 F-FDG for evaluation of abdominal malignancies. Although high uptake of 68 Ga-FAPI helps to improve lesion identification, it may lead to a higher false-positive rate. Guo et al.
(2) reported 3 false-positive cases caused by 68 Ga-FAPI, including 1 pulmonary inflammatory granuloma, 1 pulmonary infection, and 1 thyroid adenoma, which also showed high uptake on 18 F-FDG. In addition, there were 4 cases of high 68 Ga-FAPI uptake due to postoperative infection, which was mistaken as an indication of tumor recurrence. Nonspecific fibrosis induced by inflammation may contribute to the positive uptake of 68 43,44).
False-positive uptake of 68 Ga-FAPI has been observed in inflammatory diseases (e.g., uteritis and abscesses), granulomatous diseases (e.g., tuberculosis), and other diseases in which the fibrotic response is activated (e.g., myelofibrosis and cirrhosis) (28). Thus, 68 Ga-FAPI PET/CT might be problematic when differentiating between residual and/or recurrent disease and postradiation and/or postoperative inflammatory reactions (43).
In addition to comparing 68 Ga-FAPI and 18 F-FDG in the primary staging and recurrence of APM, this study also evaluated their efficacy in non-primary tumors. In non-primary tumors, 68 Ga-FAPI had a higher SEN, SPE, DOR, and AUC than 18 F-FDG. However, the various effect indicators showed a high level of heterogeneity (all P <0.05). Consequently, lymph nodes and distant metastases were subgroup analyzed to improve performance and heterogeneity. From our combined results, 68 Ga-FAPI outperforms 18 F-FDG in all aspects. It is important to note, however, that the pooled SEN of these two types of imaging agents in evaluating lymph nodes is generally unsatisfactory, with effect sizes less than 50%. In the study by Fu et al. (18), the coincidence rates of 68 Ga-FAPI and 18 F-FDG in lymph node staging were 50% and 45.4%, respectively, compared with pathology. 68 Ga-FAPI and 18 F-FDG PET/CT had the same low SEN (58.3% vs. 41.7%) and moderate DOR (77.3% vs. 63.6%), although the SPE was high (100% vs. 90%) in their study. In comparison with 18 F-FDG, 68 Ga-FAPI-04 PET detected more suspicious lymph node lesions but did not improve lymph node staging clinically (18). Gundogȃn et al. (27) found that the SEN and SPE of 68 Ga-FAPI-04 PET/CT in detecting lymph node metastasis were 100% and 95.2%, respectively, while those of 18 F-FDG PET/CT were 71.4% and 93.7%, respectively. In the study of Lin et al. (34), 68 Ga-FAPI PET/CT found only 20 true positives in 625 resected lymph nodes, with a calculated SEN of 19.2%. Therefore, FAPI has a strong ability to exclude lymph node metastases but has an unstable and limited ability to detect lymph node metastases. Its expression has been associated with multiple factors, such as local tumor invasion, lymph node metastasis, and poor prognosis, including tumor invasion, metastasis, and angiogenesis (8). Therefore, the high variability of 68 Ga-FAPI in lymph node stage assessment (pooled SEN 38.9%-45.3%) may be unexpected, especially given that the lymph nodes usually consist of mesh cell networks of the fiber layer (6). Its relatively low performance in detecting lymph node metastasis may be related to the biological characteristics of the cancer and the degree of lymph node cell enrichment (6). It has been suggested that reflective isotopes used for FAPI labeling may affect the image resolution and thus the detectability of smaller tumor aggregates in lymph nodes, because the 68 Ga (3.5 mm) positrons have a larger average range in water than those of 18 F (0.6 mm) (45).
Distant metastases of APMs occur in the liver, bone, lung, peritoneum and adrenal gland. The results of this study showed that 68 Ga-FAPI was also better than 18 F-FDG in the assessment of distant metastasis. Peritoneal metastases are common in APMs and can cause uncontrolled disease and even death (2). The uptake of 68 Ga-FAPI-04 by peritoneal metastatic lesions is so avid that FAPI-04 clearly delineates and sensitively detects lesions (18). In a singlecenter retrospective study (18), the rate of positive detection of peritoneal metastases with 68 Ga-FAPI was 93.2%, significantly higher than that with 18 F-FDG (53.8%). Their results are similar to ours. In addition, the researchers reported that 68 Ga-FAPI-04 PET/ CT accurately detected advanced peritoneal lesions with a peritoneal cancer index ≥20 in 12 patients, all of whom were underestimated by 18 F-FDG PET/CT (12/26 vs. 0/26, P < 0.001). It has been reported that a peritoneal cancer index score of 20 or more usually indicates a poor prognosis and the need for more aggressive treatment (46). This finding may be attributed to the invasion of peritoneal tissue by the tumor, which triggers a fibrotic response that leads to severe fibrosis (2). Thus, the advantage of FAPI in detecting peritoneal metastases of tumors may have a positive impact on patient management (47) and may be a promising tool for the assessment of peritoneal carcinomas (2,18). FAPI PET/CT also shows strong potential for detecting liver, bone, and other metastases. The SUVmax and TBR of bone metastases in 68 Ga-FAPI were significantly higher than those in 18 F-FDG (p<0.001) (26). In the study of Fu et al. (18), 68 Ga-FAPI and 18 F-FDG showed similar abilities to detect bone metastases (108 vs. 104) and had complementary roles.
Heterogeneity across studies may be a potential source of bias in meta-analyses (48). The diversity of patient characteristics, methodological differences and overall quality of the study may all be sources of heterogeneity (48). Our results showed that 68 Ga-FAPI had no heterogeneity in studies assessing primary tumor staging (I 2 = 22.58%, p=0.23), but 18 F-FDG had heterogeneity (I 2 = 82.48%, p=0.00). Therefore, we performed a subgroup analysis of gastric and liver cancers in the primary tumor group and found improved heterogeneity of FAPI, while FDG remained, perhaps because more studies on FDG in tumors were not included. In the evaluation of non-primary tumors, the I 2 value of the consistency test for all statistical indicators (SEN, SPE, DOR) was greater than 50%, so random effect models were used to combine effect sizes. Publication bias is a major concern in all meta-analyses, as studies reporting significantly positive results are more likely to be published than studies reporting negative results (49). In our meta-analysis, we used Deek funnel plots and Egger's test to assess publication bias. Regardless of whether primary tumor staging or non-primary tumor metastases were detected, the funnel plots showed symmetry, indicating that there was no publication bias.
Our meta-analysis is innovative, and it is the first head-to-head comparison of the application of 68 Ga-FAPI and 18 F-FDG PET/CT to APMs. We evaluated not only the primary staging of 68 Ga-FAPI and 18 F-FDG PET/CT in the primary tumors but also the application of lymph nodes and distant metastases. We assessed the quality of the included studies using the QUADAS-2 tool; and no study was considered of low quality, and the overall quality of the studies was satisfactory. Certainly, our meta-analysis has some limitations. First, the number of published articles in the field was relatively small, which may be a source of bias. Second, heterogeneity among studies may affect the performance of pooled results. This may be because the subjects included in our study had tumors in different regions of the abdominal and pelvic cavities, with many types of diseases, but this was remedied after subgroup analysis. Third, there were many differences in the sample size and study design of the included studies, which may affect the reliability of the results. The high quality evidence provided by this meta-analysis may pave the way for opening the discussion on a change in the current diagnostic paradigm for solid gastrointestinal tumours. FAPI-imaging may be soon the standard of care in these tumours, given its advantages over FDG-imaging in this setting (50). However, generation of highquality evidence is still warranted.

Conclusions
Our meta-analysis showed that 68 Ga-FAPI and 18 F-FDG PET/CT had a high overall diagnostic performance in detecting the primary staging and non-primary tumor metastasis of APMs, but the detection ability of 68 Ga-FAPI was significantly higher than that of 18 F-FDG. However, the ability of 68 Ga-FAPI to diagnose lymph node metastasis is not very satisfactory, and is significantly lower than that of distant metastasis. In the future, 68 Ga-FAPI will be a promising imaging model that may replace 18 F-FDG for APM, but this still needs to be further confirmed by multicenter, large-sample, and prospective studies.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Funding
This study was supported by Chongqing Regional Key Disciplines (Medical Imaging) (zdxk202116) and 2022 Hospital-level Scientific Research Project of Chongqing University Three Gorges Hospital (2022YJKYXM-021).